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Cytotoxic and Apoptotic Effect of Structurally Similar Flavonoids on Parental and Drug-Resistant Cells of a Human Cervical Carcinoma

Flavonoids are phytochemicals characterized by a wide range of biological activities, including antioxidant activity, the ability to modulate enzyme or cell receptor activity patterns, and to interfere with essential biochemical pathways. Using HeLa cells of a human cervical carcinoma, and their drug-resistant HeLa CK subline, the effects of three structurally related flavonoids (quercetin, fisetin and luteolin) have been examined, in terms of their: (i) cytotoxicity, (ii) influence on intracellular glutathione (GSH) level, (iii) influence on glutathione S-transferase (GST) activity, and (iv) influence on the expression of apoptosis- related genes (PARP, Bcl-2, survivin). Fisetin was more toxic to resistant HeLa CK cell line than to parental cell line, causing decreased expression of survivin in the same cell line. Concentrations of 5 mM of the examined flavonoids caused PARP degradation in parental cell line, leading HeLa cell line into apoptotic cell death. The same event was not determined in the resistant cell line. Fisetin and luteolin induce glutathione and GST in the resistant cell line, pointing to complex cellular effects which could be responsible for higher sensitivity of the resistant cell line in comparison with the parental cell line. Prooxidative nature of the investigated flavonoids was not detected, so free radical formation is not responsible for the induction of GSH, GST and proapoptotic enzymes.

apoptosis; drug-resistant cells; flavonoids; glutathione; glutathione S-transferase

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